Bronchodilating compositions and methods

ABSTRACT

Bronchodilating compositions and methods are provided. The compositions are intended for administration as a nebulized aerosol. In certain embodiments, the compositions contain formoterol, or a derivative thereof. Methods for treatment, prevention, or amelioration of one or more symptoms of bronchoconstrictive disorders using the compositions provided herein are also provided.

RELATED APPLICATIONS

[0001] This application is a divisional application of U.S. applicationSer. No. 09/887,281, to Banerjee et al., entitled “BRONCHODILATINGCOMPOSITIONS AND METHODS,” filed Jun. 22, 2001. This application alsoclaims the benefit of priority under 35 U.S.C. §119(e) to U.S.provisional patent application serial No. 60/284,606; filed April 17,2001, to Pham et al., entitled “BRONCHODILATING COMPOSITIONS ANDMETHODS.” U.S. application Ser. No. 09/887,281 claims benefit ofpriority under 35 U.S.C. §119(e) to U.S. provisional patent applicationserial No. 60/284,606. The disclosures of the above-referencedapplications are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

[0002] Compositions and methods are provided relating to treatment,prevention, or amelioration of one or more symptoms ofbronchoconstrictive disorders. In particular, the compositions andmethods herein include formoterol, and/or derivatives thereof. Thecompositions are propellant-free, sterile unit dose or multidoseinhalation solutions intended for administration via nebulization.

BACKGROUND OF THE INVENTION

[0003] Bronchoconstrictive disorders affect millions worldwide. Suchdisorders include asthma (including bronchial asthma, allergic asthmaand intrinsic asthma, e.q., late asthma and airwayhyper-responsiveness), chronic bronchitis and other chronic obstructivepulmonary diseases. Compounds having β₂-adrenoreceptor agonist activityhave been developed to treat these conditions. Such compounds include,but are not limited to, Albuterol(α¹-(((1,1-dimethylethyl)amino)methyl)-4-hydroxy-1,3-benzenedimethanol);Bambuterol (dimethylcarbamic acid5-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,3-phenylene ester);Bitolterol (4-methylbenzoic acid4-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,2-phenylene ester);Broxaterol(3-bromo-α-(((1,1-dimethylethyl)amino)-methyl)-5-isoxazolemethanol);Isoproterenol(4-(1-hydroxy-2-((1-methyl-ethyl)amino)ethyl)-1,2-benzenediol);Trimetoquinol(1,2,3,4-tetrahydro-1-((3,4,5-trimethoxyphenyl)methyl)-6,7-isoquinolinediol);Clenbuterol(4-amino-3,5-dichloro-α-(((1,1-diemthylethyl)amino)methyl)benzenemethanol);Fenoterol(5-(1-hydroxy-2-((2-(4-hydroxyphenyl)-1-methylethyl)-amino)ethyl)-1,3-benzenediol);Formoterol(2-hydroxy-5-((1RS)-1-hydroxy-2-(((1RS)-2-(p-methoxyphenyl)-1-methylethyl)amino)ethyl)formanilide);(R,R)-Formoterol; Desformoterol ((R,R) or(S,S)-3-amino-4-hydroxy-α-(((2-(4-methoxyphenyl)-1-methylethyl)amino)methyl)benzenemethanol); Hexoprenaline(4,4′-(1,6-hexanediyl)-bis(imino(1-hydroxy-2,1-ethanediyl)))bis-1,2-benzenediol);Isoetharine(4-(1-hydroxy-2-((1-methylethyl)amino)-butyl)-1,2-benzenediol);Isoprenaline(4-(1-hydroxy-2-((1-methylethyl)-amino)ethyl)-1,2-benzenediol);Metaproterenol(5-(1-hydroxy-2-((1-methyl-ethyl)amino)ethyl)-1,3-benzenediol);Picumeterol(4-amino-3,5-dichloro-α-(((6-(2-(2-pyridinyl)ethoxy)hexyl)amino)methyl)benzenemethanol);Pirbuterol(α⁶-(((1,1-dimethylethyl)amino)methyl)-3-hydroxy-2,6-pyridine-methanol);Procaterol(((R*,S*)-(±)-8-hydroxy-5-(1-hydroxy-2-((1-methylethyl)amino)butyl)-2(1H)-quinolinone);Reproterol ((7-(3-((2-(3,5-dihydroxyphenyl)-2-hydroxyethyl)amino)propyl)-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione); Rimiterol(4-(hydroxy-2-piperidinylmethyl)-1,2-benzenediol); Salbutamol((±)-α¹-(((1,1-dimethylethyl)amino)methyl)-4-hydroxy-1,3-benzenedimethanol);(R)-Salbutamol; Salmeterol((±)-4-hydroxy-α¹-(((6-(4-phenylbutoxy)hexyl)amino)methyl)-1,3-benzenedimethanol);(R)-Salmeterol; Terbutaline(5-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,3-benzenediol);Tulobuterol(2-chloro-α-(((1,1-dimethylethyl)amino)methyl)benzenemethanol); andTA-2005(8-hydroxy-5-((1R)-1-hydroxy-2-(N-((1R)-2-(4-methoxyphenyl)-1-methylethyl)amino)ethyl)-carbostyrilhydrochloride).

[0004] These compounds are typically formulated for inhalation therapy.Aqueous or liquid formulations are preferred over solid formulations.Powdered formulations are more difficult to administer, particularly tothe young and elderly who are most often the patients in need of suchtherapy. Compounds, such as formoterol, which has many desirableproperties, are not adequately stable in aqueous solutions to beformulated as liquids. Hence there is a need for formulations ofcompounds, such as formoterol, in a form that can be convenientlyadministered and that are stable for extended periods of time.Therefore, it is an object herein to provide liquid formulations ofβ₂-adrenoreceptor agonist compounds. It is also an object herein toprovide more stable formulations of others of these compounds.

SUMMARY OF THE INVENTION

[0005] Compositions and methods for treatment, prevention, oramelioration of one or more symptoms of bronchoconstrictive disordersare provided. The compositions provided herein are stable solutions of abronchodilating agent, or a derivative thereof, in a pharmacologicallysuitable fluid that contains water, that are stable during long termstorage. The compositions are suitable for direct administration to asubject in need thereof. Pharmacologically suitable fluids include, butare not limited to, polar fluids, including protic fluids. In certainembodiments herein, the compositions are aqueous solutions.

[0006] The compositions provided herein possess an estimated shelf-lifeof greater than 1, 2 or 3 months usage time at 25° C. and greater thanor equal to 1, 2 or 3 years storage time at 5° C. In certain of theseembodiments, using Arrhenius kinetics, >80% or >85% or >90% or >95%estimated bronchodilating agent remains after such storage. Thesecompositions are particularly useful for administration vianebulization. In certain embodiments herein, the subject is a mammal. Inother embodiments, the subject is a human.

[0007] The compositions provided herein are formulated to remain stableover a relatively long period of time. For example, the compositionsprovided herein are stored between −15° C. and 25° C., or between 2° C.and 8° C., and remain stable for the desired time. In one embodiment,the compositions are stored at 5° C.

[0008] Among the bronchodilating agents for use herein are Albuterol(α¹′-(((1,1-dimethylethyl)amino)methyl)-4-hydroxy-1,3-benzenedimethanol);Bambuterol (dimethylcarbamic acid5-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,3-phenylene ester);Bitolterol (4-methylbenzoic acid4-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,2-phenylene ester);Broxaterol(3-bromo-α-(((1,1-dimethylethyl)amino)methyl)-5-isoxazolemethanol);Isoproterenol(4-(1-hydroxy-2-((1-methylethyl)amino)ethyl)-1,2-benzenediol);Trimetoquinol(1,2,3,4-tetrahydro-1-((3,4,5-trimethoxyphenyl)-methyl)-6,7-isoquinolinediol);Clenbuterol(4-amino-3,5-dichloro-α-(((1,1-diemthylethyl)amino)methyl)benzenemethanol);Fenoterol(5-(1-hydroxy-2-((2-(4-hydroxyphenyl)-1-methylethyl)amino)ethyl)-1,3-benzenediol);Formoterol(2-hydroxy-5-((1RS)-1-hydroxy-2-(((1RS)-2-(p-methoxyphenyl)-1-methylethyl)amino)ethyl)formanilide);(R,R)-Formoterol; Desformoterol ((R,R) or(S,S)-3-amino-4-hydroxy-α-(((2-(4-methoxyphenyl)-1-methylethyl)amino)methyl)benzenemethanol);Hexoprenaline(4,4′-(1,6-hexanediyl)-bis(imino(1-hydroxy-2,1-ethanediyl)))bis-1,2-benzenediol);Isoetharine (4-(1-hydroxy-2-((1-methylethyl)amino)butyl)-1,2-benzenediol); Isoprenaline(4-(1-hydroxy-2-((1-methylethyl)amino)ethyl)-1,2-benzenediol);Metaproterenol(5-(1-hydroxy-2-((1-methylethyl)amino)ethyl)-1,3-benzenediol);Picumeterol(4-amino-3,5-dichloro-α-(((6-(2-(2-pyridinyl)ethoxy)hexyl)-amino)methyl)benzenemethanol);Pirbuterol(α⁶-(((1,1-dimethylethyl)-amino)methyl)-3-hydroxy-2,6-pyridinemethanol);Procaterol(((R*,S*)-(±)-8-hydroxy-5-(1-hydroxy-2-((1-methylethyl)amino)butyl)-2(1H)-quinolinone);Reproterol((7-(3-((2-(3,5-dihydroxyphenyl)-2-hydroxyethyl)amino)-propyl)-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione);Rimiterol (4-(hydroxy-2-piperidinylmethyl)-1,2-benzenediol); Salbutamol((±)-α¹-(((1,1-dimethylethyl)amino)methyl)-4-hydroxy-1,3-benzenedimethanol);(R)-Salbutamol; Salmeterol((±)-4-hydroxy-α¹-(((6-(4-phenylbutoxy)hexyl)-amino)methyl)-1,3-benzenedimethanol);(R)-Salmeterol; Terbutaline(5-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,3-benzenediol);Tulobuterol(2-chloro-α-(((1,1-dimethylethyl)amino)methyl)benzenemethanol); andTA-2005(8-hydroxy-5-((1R)-1-hydroxy-2-(N-((1R)-2-(4-methoxyphenyl)-1-methylethyl)amino)ethyl)carbostyrilhydrochloride).

[0009] Of particular interest herein is formoterol, having the formula:

[0010] Formoterol for use in the compositions and methods providedherein includes2-hydroxy-5-((1RS)-1-hydroxy-2-(((1RS)-2-(p-methoxy-phenyl)-1-methylethyl)amino)ethyl)formanilide;or a stereoisomer thereof; and also includes the single enantiomers2-hydroxy-5-((1 S)-1-hydroxy-2-(((1S)-2-(p-methoxyphenyl)-1-methylethyl)amino)ethyl)formanilide and2-hydroxy-5-((1R)-1-hydroxy-2-(((1R)-2-(p-methoxyphenyl)-1-methylethyl)-amino)ethyl)formanilide.

[0011] In certain embodiments, the compositions are administered vianebulization. Administration of a nebulized aerosol is preferred overthe use of dry powders for inhalation in certain subject populations,including pediatric and geriatric groups.

[0012] In one embodiment, the compositions for use in the methodsprovided herein contain a pharmaceutically acceptable derivative offormoterol. In another embodiment, the compositions for use in themethods provided herein contain a pharmaceutically acceptable salt offormoterol. Pharmaceutically acceptable salts include, but are notlimited to, salts of mineral acids, such as but not limited tohydrochlorides and sulfates; and salts of organic acids, such as but notlimited to acetates, lactates, malates, tartrates, citrates, ascorbates,succinates, butyrates, valerates and fumarates. In one embodiment, thecompositions for use in the methods provided herein contain formoterolfumarate or formoterol fumarate dihydrate. In another embodiment, thecompositions for use in the methods provided herein contain formoteroltartrate.

[0013] Also provided herein are combinations containing a compositionprovided herein and a nebulizer. The combinations can be packaged askits, which optionally contain other components, including instructionsfor use of the nebulizer. Any nebulizer is contemplated for use in thekits and methods provided herein. In particular, the nebulizers for useherein nebulize liquid formulations, including the compositions providedherein, containing no propellant. The nebulizer may produce thenebulized mist by any method known to those of skill in the art,including, but not limited to, compressed air, ultrasonic waves, orvibration. The nebulizer may further have an internal baffle. Theinternal baffle, together with the housing of the nebulizer, selectivelyremoves large droplets from the mist by impaction and allows thedroplets to return to the reservoir. The fine aerosol droplets thusproduced are entrained into the lung by the inhaling air/oxygen.

[0014] Methods for the treatment, prevention, or amelioration of one ormore symptoms of bronchoconstrictive disorders, including, but notlimited to, asthma, including, but not limited to, bronchial asthma,allergic asthma and intrinsic asthma, e.q., late asthma and airwayhyper-responsiveness; chronic bronchitis; and other chronic obstructivepulmonary diseases are provided. The methods involve administering aneffective amount of a pharmaceutical composition provided herein to asubject in need of such treatment.

[0015] Articles of manufacture, containing packaging material, acomposition provided herein, which is useful for treatment, preventionor amelioration of one or more symptoms of diseases or disordersassociated with undesired and/or uncontrolled bronchoconstriction, and alabel that indicates that the composition is used for treatment,prevention or amelioration of one or more symptoms of diseases ordisorders associated with undesired and/or uncontrolledbronchoconstriction, are also provided.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0016] Definitions

[0017] Unless defined otherwise, all technical and scientific terms usedherein have the same meaning as is commonly understood by one ofordinary skill in the art to which this invention belongs. All patents,applications, published applications and other publications areincorporated by reference in their entirety. In the event that there area plurality of definitions for a term herein, those in this sectionprevail unless stated otherwise.

[0018] As used herein, formoterol refers to2-hydroxy-5-((1RS)-1-hydroxy-2-(((1RS)-2-(p-methoxyphenyl)-1-methylethyl)amino)ethyl)formanilide;or a stereoisomer thereof. The term formoterol also refers to the singleenantiomers 2-hydroxy-5-((1 S)-1-hydroxy-2-(((1S)-2-(p-methoxyphenyl)-1-methylethyl)amino)ethyl)formanilide and2-hydroxy-5-((1R)-1-hydroxy-2-(((1R)-2-(p-methoxyphenyl)-1-methylethyl)amino)ethyl)formanilide.

[0019] As used herein, formoterol fumarate refers to a salt offormoterol having the formula (formoterol).½ fumarate.

[0020] As used herein, formoterol free base refers to the neutral,anhydrous form of formoterol. Thus, a recitation that a compositioncontains, e.q., 59 μg/mL of formoterol free base means that thecomposition contains 59 μg/mL of neutral, anhydrous formoterol. Suchcompositions may be prepared using a derivative of formoterol.

[0021] As used herein, an aerosol is liquid or particulate matterdispersed in air. Aerosols include dispersions of liquids, includingaqueous and other solutions, and solids, including powders, in air.

[0022] As used herein, a nebulized solution refers to a solution that isdispersed in air to form an aerosol. Thus, a nebulized solution is aparticular form of an aerosol.

[0023] As used herein, a nebulizer is an instrument that is capable ofgenerating very fine liquid droplet for inhalation into the lung. Withinthis instrument, the nebulizing liquid or solution is atomized into amist of droplets with a broad size distribution by methods known tothose of skill in the art, including, but not limited to, compressedair, ultrasonic waves, or a vibrating orifice. Nebulizers may futhercontain, e.q., a baffle which, along with the housing of the instrument,selectively removes large droplets from the mist by impaction. Thus, themist inhaled into the lung contains fine aerosol droplets.

[0024] As used herein, a pharmacologically suitable fluid is a solventsuitable for pharmaceutical use which is not a liquified propellant gas.Exemplary pharmacologically suitable fluids include polar fluids,including protic fluids such as water.

[0025] As used herein, a combination refers to any association betweentwo or among more items.

[0026] As used herein, fluid refers to any composition that can flow.Fluids thus encompass compositions that are in the form of semi-solids,pastes, solutions, aqueous mixtures, gels, lotions, creams and othersuch compositions.

[0027] As used herein, a mixture is a mutual incorporation of two ormore substances, without chemical union, the physical characteristics ofeach of the components being retained.

[0028] As used herein, the stability of a composition provided hereinrefers to the length of time at a given temperature that greater than80%, 85%, 90% or 95% of the initial amount of active ingredient, e.g.,formoterol, is present in the composition. Thus, for example, acomposition that is stable for 30 days at 25° C. would have greater than80%, 85%, 90% or 95% of the initial amount of active ingredient presentin the composition at 30 days following storage at 25° C.

[0029] As used herein, pharmaceutically acceptable derivatives of acompound include salts, esters, enol ethers, enol esters, acids, bases,solvates, hydrates or prodrugs thereof. Such derivatives may be readilyprepared by those of skill in this art using known methods for suchderivatization. The compounds produced may be administered to animals orhumans without substantial toxic effects and either are pharmaceuticallyactive or are prodrugs. Pharmaceutically acceptable salts include, butare not limited to, amine salts, such as but not limited toN,N′-dibenzylethylenediamine, chloroprocaine, choline, ammonia,diethanolamine and other hydroxyalkylamines, ethylenediamine,N-methylglucamine, procaine, N-benzylphenethylamine,1-para-chlorobenzyl-2-pyrrolidin-1′-ylmethylbenzimidazole, diethylamineand other alkylamines, piperazine and tris(hydroxymethyl)aminomethane;alkali metal salts, such as but not limited to lithium, potassium andsodium; alkali earth metal salts, such as but not limited to barium,calcium and magnesium; transition metal salts, such as but not limitedto zinc; and other metal salts, such as but not limited to sodiumhydrogen phosphate and disodium phosphate; and also including, but notlimited to, salts of mineral acids, such as but not limited tohydrochlorides and sulfates; and salts of organic acids, such as but notlimited to acetates, lactates, malates, tartrates, citrates, ascorbates,succinates, butyrates, valerates and fumarates. Pharmaceuticallyacceptable esters include, but are not limited to, alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl andheterocyclyl esters of acidic groups, including, but not limited to,carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids,sulfinic acids and boronic acids. Pharmaceutically acceptable enolethers include, but are not limited to, derivatives of formula C═C(OR)where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl,heteroaralkyl, cycloalkyl ar heterocyclyl. Pharmaceutically acceptableenol esters include, but are not limited to, derivatives of formulaC═C(OC(O)R) where R is hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, aralkyl, heteroaralkyl, cycloalkyl ar heterocyclyl.Pharmaceutically acceptable solvates and hydrates are complexes of acompound with one or more solvent or water molecule, in certainembodiments 1 to about 100, in other embodiments 1 to about 10, infurther embodiments one to about 2, 3 or 4, solvent or water molecules.Formoterol salts and hydrates are used in certain embodiments herein.

[0030] As used herein, treatment means any manner in which one or moreof the symptoms of a condition, disorder or disease are ameliorated orotherwise beneficially altered. Treatment also encompasses anypharmaceutical use of the compositions herein, such as use for treatingcancer.

[0031] As used herein, amelioration of the symptoms of a particulardisorder by administration of a particular pharmaceutical compositionrefers to any lessening, whether permanent or temporary, lasting ortransient that can be attributed to or associated with administration ofthe composition.

[0032] As used herein, a prodrug is a compound that, upon in vivoadministration, is metabolized or otherwise converted to thebiologically, pharmaceutically or therapeutically active form of thecompound. To produce a prodrug, the pharmaceutically active compound ismodified such that the active compound will be regenerated by metabolicprocesses. The prodrug may be designed to alter the metabolic stabilityor the transport characteristics of a drug, to mask side effects ortoxicity, to improve the flavor of a drug or to alter othercharacteristics or properties of a drug. By virtue of knowledge ofpharmacodynamic processes and drug metabolism in vivo, those of skill inthis art, once a pharmaceutically active compound is known, can designprodrugs of the compound (see, e.g., Nogrady (1985) Medicinal ChemistryA Biochemical Approach, Oxford University Press, New York, pages388-392).

[0033] It is to be understood that the compounds for use in thecompositions and methods provided herein may contain chiral centers.Such chiral centers may be of either the (R) or (S) configuration, ormay be a mixture thereof. Thus, the compounds for use in thecompositions provided herein may be enantiomerically pure, or bestereoisomeric or diastereomeric mixtures. It is to be understood thatthe chiral centers of the compounds provided herein may undergoepimerization in vivo. Thus, one of skill in the art will recognize thatadministration of a compound in its (R) form is equivalent, forcompounds that undergo epimerization in vivo, to administration of thecompound in its (S) form.

[0034] As used herein, bronchoconstriction refers to a reduction in thecaliber of a bronchus or bronchi.

[0035] As used herein, undesired and/or uncontrolled bronchoconstrictionrefers to bronchoconstriction that results in or from a pathologicalsymptom or condition. Pathological conditions include, but are notlimited to, asthma and chronic obstructive pulmonary disease (COPD).Pathological symptoms include, but are not limited to, asthma and COPD.

[0036] As used herein, the statement that a composition is stable during“long term storage” means that the composition is suitable foradministration to a subject in need thereof when it has an estimatedshelf-life of greater than 1, 2 or 3 months usage time at 25° C. andgreater than or equal to 1, 2 or 3 years storage time at 5° C. Incertain embodiments herein, using Arrhenius kinetics, >80% or >85%or >90% or >95% estimated bronchodilating agent remains after suchstorage.

[0037] A. Formoterol

[0038] Formoterol(2-hydroxy-5-((1RS)-1-hydroxy-2-(((1RS)-2-(p-methoxy-phenyl)-1-methylethyl)amino)ethyl)formanilide)is derived from adrenaline and, as noted above, is used as aβ₂-stimulator in inhalation therapy of respiratory diseases,particularly for the treatment of bronchial asthma. It has been reportedthat in patients with reversible obstructive respiratory diseases,formoterol has a bronchodilatory effect. This effect has a relativelyrapid onset (approximately 1-3 minutes) and a relatively long duration(greater than 12 hours). Formoterol inhibits the release of leukotrienesand other messenger substances involved with inflammation, such ashistamines. In addition, formoterol may bring about a hyperglycaemicactivity.

[0039] To date, formoterol has been formulated as a dry powder andadministered via devices such as the Turbuhaler® and the Aerolizer®.See, e.g., Seberova et al. (2000) Respir. Med. 94(6):607-611; Lotvall etal. (1999) Can. Respir. J. 6(5):412-416; Campbell et al. (1999) Respir.Med. 93(4):236-244; Nightingale et al (1999) Am. J. Respir. Crit. CareMed. 159(6):1786-1790; Lecaillon et al. (1999) Eur. J. Clin. Pharmacol.55(2):131-138; Bartow et al. (1998) Drugs 55(2):303-322; Ekstrom et al.(1998) Respir. Med. 92(8):1040-1045; Ringdal et al. (1998) Respir. Med.92(8):1017-1021; Totterman et al. (1998) Eur. Respir. J. 12(3):573-579;Palmqvist et al. (1997) Eur. Respir. J. 10(11):2484-2489; Nielsen et al.(1997) Eur. Respir. J. 10(9):2105-2109; Ullman et al. (1996) Allergy51(10):745-748; Selroos et al. (1996) Clin. Immunother. 6:273-299; andSchreurs et al. (1996) Eur. Respir. J. 9(8):1678-1683.

[0040] Formoterol is also available as a tablet and a dry syrup incertain areas of the world (e.g., Atock®, marcketed by YamanouchiPharmaceutical Co. Ltd., Japan). Formoterol formulations are alsoavailable in other areas (e.q., Europe and U.S.) for propellant-basedmetered dose inhalers and dry powder inhalers (e.g., Turbuhaler®,Aerolizer® and Foradil Aerolizer®). None of these formulations are waterbased. Sterile, stable, aqueous based inhalation solutions of formoterolfor nebulization are not available, nor have they been reported.

[0041] Compositions containing formoterol in combination with otheractive ingredients have been disclosed. See, e.g., U.S. Pat. Nos.6,004,537, 5,972,919 and 5,674,860 (formoterol and budenoside), U.S.Pat. Nos. 5,668,110, 5,683,983, 5,677,280 and 5,654,276 (formoterol andIL-5 inhibitors), U.S. Pat. No. 6,136,603 (formoterol and antisensemodulators of IL-5), U.S. Pat. No. 5,602,110 (formoterol andmillrinone), U.S. Pat. No. 5,525,623 (formoterol and a tryptaseinhibitor), U.S. Pat. Nos. 5,691,336, 5,877,191, 5,929,094, 5,750,549and 5,780,467 (formoterol and a tachykinin receptor antagonist); andInternational Patent Application Publication Nos. WO 99/00134(formoterol and rofleponide) and WO 99/36095 (formoterol and a dopamineD₂ receptor agonist).

[0042] Other compositions containing formoterol have been disclosed inU.S. Pat. Nos. 5,677,809, 6,126,919, 5,733,526, 6,071,971, 6,068,833,5,795,564, 6,040,344, 6,041,777, 5,874,481, 5,965,622 and 6,161,536.

[0043] U.S. Pat. No. 6,150,418 discloses a “liquid active substanceconcentrate” containing formoterol in the form of its free base or inthe form of one of the pharmacologically acceptable salts or additionproducts (adducts) thereof as active substance. This “liquid activesubstance concentrate” is reported to be a concentrated (i.e., greaterthan 10 mg/mL, preferably 75 to 500 mg/mL) solution or suspension thatis stable for a period of several months possibly up to several yearswithout any deterioration in the pharmaceutical quality. This patentteaches that it is the high concentration that allows for the stabilityof the concentrate. The “liquid active substance concentrate” is notsuitable for direct administration to a patient.

[0044] U.S. Pat. No. 6,040,344 discloses an aqueous aerosol formulationof formoterol tartrate for use in a nebulizer. This patent states thatthe formulation disclosed therein is not attractive for long termstorage.

[0045] B. Compositions for Use in Treatment, Prevention, or Ameliorationof One or More Symptoms of Bronchoconstrictive Disorders

[0046] Pharmaceutical compositions containing a β₂-adrenoreceptoragonist for administration via nebulization are provided. Thecompositions are sterile filtered and filled in vials, including unitdose vials providing sterile unit dose formulations which are used in anebulizer and suitably nebulized. Each unit dose vial is sterile and issuitably nebulized without contaminating other vials or the next dose.

[0047] The unit dose vials are formed in a form-fill-seal machine or byany other suitable method known to those of skill in the art. The vialsmay be made of plastic materials that are suitably used in theseprocesses. For example, plastic materials for preparing the unit dosevials include, but are not limited to, low density polyethylene, highdensity polyethylene, polypropylene and polyesters. In one embodiment,the plastic material is low density polyethylene.

[0048] In one embodiment, the β₂-adrenoreceptor agonist in formoterol,or a pharmaceutically acceptable derivative thereof. In otherembodiments, the formoterol for use in the compositions provided hereinis formoterol fumarate. Formoterol refers to2-hydroxy-5-((1RS)-1-hydroxy-2-(((1RS)-2-(p-methoxyphenyl)-1-methylethyl)amino)ethyl)formanilide;or a stereoisomer thereof. The term formoterol also refers herein to thesingle enantiomers 2-hydroxy-5-((1 S)-1-hydroxy-2-(((1S)-2-(p-methoxyphenyl)-1-methylethyl)amino)ethyl)formanilide and2-hydroxy-5-((1R)-1-hydroxy-2-(((1R)-2-(p-methoxyphenyl)-1-methylethyl)amino)ethyl)formanilide.

[0049] In one embodiment, the compositions contain formoterol free baseat a concentration of about 5 μg/mL to about 2 mg/mL. In otherembodiments, the maximum concentration of formoterol free base in thecompositions is 1.5 mg/mL. In further embodiments, the concentration offormoterol free base in the compositions is about 10 μg/mL to about 1mg/mL, or about 50 μg/mL to about 200 μg/mL. In other embodiments, thecompositions contain formoterol fumarate at a concentration of about 80μg/mL up to about 175 to 200 μg/mL. In further embodiments, thecompositions contain formoterol fumarate at a concentration of about 90μg/mL up to about 125 to 150 μg/mL. The formoterol fumarate isformulated, in certain compositions provided herein, at a concentrationof about 100 μg/mL. The formoterol fumarate is formulated, in othercompositions provided herein, at a concentration of about 85 μg/mL orabout 170 μg/mL. In one embodiment, the formoterol fumarate isformulated for single dosage administration via nebulization at aconcentration of about 100 μg/mL. In another embodiment, thecompositions contain formoterol free base at a concentration of about 40to about 150 μg/mL, particularly about 59 or about 118 μg/mL.

[0050] The compostions containing the β₂-adrenoreceptor agonist,including formoterol, are formulated with a pharmacologically suitablefluid. Pharmacologically suitable fluids include, but are not limitedto, polar solvents, including, but not limited to, compounds thatcontain hydroxyl groups or other polar groups. Such solvents include,but are not limited to, water or alcohols, such as ethanol, isopropanol,and glycols including propylene glycol, polyethylene glycol,polypropylene glycol, glycol ether, glycerol and polyoxyethylenealcohols.

[0051] Polar solvents also include protic solvents, including, but notlimited to, water, aqueous saline solutions with one or morepharmaceutically acceptable salt(s), alcohols, glycols or a mixturethereof. For a saline solution as the solvent or as a component thereof,particularly suitable salts are those which display no or onlynegligible pharmacological activity after administration.

[0052] In the embodiments herein, the compositions have a pH of about2.0 to about 8.0. In other embodiments, the compositions have a pH ofabout 4.0 to about 6.0, or about 4.5 to about 5.5. In certain of theabove embodiments, the compositions are formulated at a pH of about 4,4.4 or 4.6 up to about 5.5, 5.7 or 6. In other embodiments, the pH isabout 5.0. It has been found herein that the rate constant fordecomposition of an aqueous solution of formoterol is dependent on pH.The rate constant (k_(obs)) at 60° C. at a pH of 3, 4, 5 and 7 isapproximately 0.62, 0.11, 0.044 and 0.55 day⁻¹, respectively. Therefore,the decomposition of formoterol in aqueous solution at 60° C. at abuffer concentration of 5 mM and an ionic strength of 0.05 is slowest ata pH of about 5.0.

[0053] The solubility of formoterol in aqueous solution has been foundherein to be dependent on pH. Thus, at a pH of between about 5 and about7, the aqueous solubility of formoterol at ambient temperature isapproximately 2.2 mg/mL. At a pH of about 4, the aqueous solubility offormoterol at ambient temperature is approximately 3 mg/mL, while at apH of about 3, the aqueous solubility of formoterol at ambienttemperature is about 4.8 mg/mL. The solubility of formoterol in purewater, for example, high performance liquid chromatography (HPLC) water,at ambient temperature is approximately 2 mg/mL.

[0054] In other of the above embodiments, the compositions furthercontain a buffer, including, but not limited to, citric acid/phosphate,acetate, barbital, borate, Britton-Robinson, cacodylate, citrate,collidine, formate, maleate, Mcllvaine, phosphate, Prideaux-Ward,succinate, citrate-phosphate-borate (Teorell-Stanhagen), veronalacetate, MES (2-(N-morpholino)ethanesulfonic acid), BIS-TRIS(bis(2-hydroxyethyl)iminotris-(hydroxymethyl)methane), ADA(N-(2-acetamido)-2-iminodiacetic acid), ACES(N-(carbamoylmethyl)-2-aminoethanesulfonaic acid), PIPES(piperazine-N,N′-bis(2-ethanesulfonic acid)), MOPSO(3-(N-morpholino)-2-hydroxypropanesulfonic acid), BIS-TRIS PROPANE(1,3-bis(tris(hydroxymethyl)methylamino)propane), BES(N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonaic acid), MOPS(3-(N-morpholino)propanesulfonic acid), TES(N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid), HEPES(N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid), DIPSO(3-(N,N-bis(2-hydroxyethyl)amino)-2-hydroxypropanesulfonicacid), MOBS(4-(N-morpholino)butanesulfonic acid), TAPSO(3-(N-tris(hydroxymethyl)methylamino)-2-hydroxypropanesulfonic acid),TRIZMA® (tris(hydroxymethyl-aminomethane), HEPPSO(N-(2-hydroxyethyl)piperazine-N′-(2-hydroxypropanesulfonic acid), POPSO(piperazine-N,N′-bis(2-hydroxypropanesulfonic acid)), TEA(triethanolamine), EPPS(N-(2-hydroxyethyl)-piperazine-N′-(3-propanesulfonic acid), TRICINE(N-tris(hydroxymethyl)methylglycine), GLY-GLY (glycylglycine), BICINE(N,N-bis(2-hydroxyethyl)glycine), HEPBS(N-(2-hydroxyethyl)piperazine-N′-(4-butanesulfonic acid)), TAPS(N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid), AMPD(2-amino-2-methyl-1,3-propanediol), and/or any other buffers known tothose of skill in the art. In one embodiment, the buffer is citricacid/phosphate buffer, acetate buffer, citrate buffer or phosphatebuffer. In another embodiment, the buffer is a citrate buffer (citricacid/sodium citrate). The buffer concentration has been found herein toaffect the stability of the composition. Buffer concentrations for useherein include from about 0 or 0.01 mM to about 150 mM, or about 1 mM toabout 20 mM. In one embodiment, the buffer concentration is about 5 mM.In other embodiments, the buffer concentration is about 1 mM to about 50mM. In one embodiment, the buffer concentration is about 20 mM. Thekinetic-pH profile of formoterol is dependent on buffer concentration.At low and approximately neutral conditions, increasing the bufferconcentration from 5 mM to 20 mM increased the rated constant ofdecomposition significantly. However, no noticeable differences in rateconstant were observed in the pH region of about 4.5 to about 5.5 withincreasing buffer concentration from 5 mM to 20 mM. The particularbuffer and buffer concentration of a given composition for long termstorage provided herein may be determined empirically using standardstability assays well known to those of skill in the art (see, e.q., theExamples).

[0055] The ionic strength of the compositions provided herein also hasbeen found herein to affect the stability of the composition. Ionicstrengths of the compositions provided herein are from about 0 to about0.4, or from about 0.05 to about 0.16. Compositions having a lower ionicstrength exhibit improved stability over formulations having higherionic strength. The rate constant of decomposition was essentially thesame at ionic strength 0.05 to 0.1, but increased to some extent ationic strength of 0.2. The particular ionic strength of a givencomposition for long term storage provided herein may be determinedempirically using standard stability assays well known to those of skillin the art (see, e.g., the Examples).

[0056] In embodiments where the pharamacologically suitable fluid is asaline solution, tonicity adjusting agents may be added to provide thedesired ionic strength. Tonicity adjusting agents for use herein includethose which display no or only negligible pharmacological activity afteradministration. Both inorganic and organic tonicity adjusting agents maybe used in the compositions provided herein. Tonicity adjusting agentsinclude, but are not limited to, ammonium carbonate, ammonium chloride,ammonium lactate, ammonium nitrate, ammonium phosphate, ammoniumsulfate, ascorbic acid, bismuth sodium tartrate, boric acid, calciumchloride, calcium disodium edetate, calcium gluconate, calcium lactate,citric acid, dextrose, diethanolamine, dimethylsulfoxide, edetatedisodium, edetate trisodium monohydrate, fluorescein sodium, fructose,galactose, glycerin, lactic acid, lactose, magnesium chloride, magnesiumsulfate, mannitol, polyethylene glycol, potassium acetate, potassiumchlorate, potassium chloride, potassium iodide, potassium nitrate,potassium phosphate, potassium sulfate, proplyene glycol, silvernitrate, sodium acetate, sodium bicarbonate, sodium biphosphate, sodiumbisulfite, sodium borate, sodium bromide, sodium cacodylate, sodiumcarbonate, sodium chloride, sodium citrate, sodium iodide, sodiumlactate, sodium metabisulfite, sodium nitrate, sodium nitrite, sodiumphosphate, sodium propionate, sodium succinate, sodium sulfate, sodiumsulfite, sodium tartrate, sodium thiosulfate, sorbitol, sucrose,tartaric acid, triethanolamine, urea, urethan, uridine and zinc sulfate.In certain embodiments, the tonicity adjusting agent is sodium chloride.In these embodiments, the pharmacologically suitable fluid is aqueoussaline.

[0057] The storage temperature of the compositions provided herein alsohas been found herein to affect the stability of the composition.Compositions stored at a lower temperature exhibit improved stabilityover formulations stored at higher temperatures. The effect oftemperature on the rate constant of decomposition at pH 5, a bufferconcentration of 5 mM, and an ionic strength of 0.05, was linearaccording to Arrhenius kinetics, i.e., when Ln k_(obs) was plottedagainst 1/T, where T is the temperature in degree Kelvin.

[0058] The estimated shelf-life of formoterol in the compositionsprovided herein is significantly greater than that reported for knownformoterol compositions. The estimated shelf-life of formoterol in thecompositions provided herein is about 6.2 years at 5° C. and about 7.5months at 25° C. The estimated formoterol concentrations in thecompositions provided herein as a function of storage time at 5° C. andusage time at 25° C. was determined. It is estimated that greater than90% of the initial formoterol present in the composition remains after 3months of usage time at 25° C. and 3 years of storage time at 5° C. aswell as after 0.5 months of usage time at 25° C. and 1 year of storagetime at 5° C.

[0059] In one embodiment, the compositions provided herein are preparedcontaining formoterol fumarate at a nominal concentration of 0.1 mg/mLat the indicated pH and citric acid/phosphate buffer concentrations. Thesolutions were stored at 60° C. In these compositions, formoterol isrelatively more stable at a pH from about 4 to about 5, and is also morestable at lower buffer concentration.

[0060] The compositions provided herein also may include excipients andadditives. The particular excipient or additive for use in thecompositions for long term storage provided herein may be determinedempirically using methods well known to those of skill in the art (see,e.g., the Examples). Excipients and additives are any pharmacologicallysuitable and therapeutically useful substance which is not an activesubstance. Excipients and additives generally have no pharmacologicalactivity, or at least no undesirable pharmacological activity. Theexcipients and additives include, but are not limited to, surfactants,stabilizers, complexing agents, antioxidants, or presevatives whichprolong the duration of use of the finished pharmaceutical formulation,flavorings, vitamins, or other additives known in the art. Complexingagents include, but are not limited to, ethylenediaminetetraacetic acid(EDTA) or a salt thereof, such as the disodium salt, citric acid,nitrilotriacetic acid and the salts thereof. In one embodiment, thecomplexing agent is EDTA. Preservatives include, but are not limited to,those that protect the solution from contamination with pathogenicparticles, including benzalkonium chloride or benzoic acid, or benzoatessuch as sodium benzoate. Antioxidants include, but are not limited to,vitamins, provitamins, ascorbic acid, vitamin E or salts or estersthereof.

[0061] The compositions provided herein also may include a cosolvent,which increases the solubility of additives or the active ingredient(s).The particular cosolvent for use in the compositions for long termstorage provided herein may be determined empirically using methods wellknown to those of skill in the art (see, e.q., the Examples). Cosolventsfor use herein include, but are not limited to, hydroxylated solvents orother polar solvents, such as alcohols such as isopropyl alcohol,glycols such as propylene glycol, polyethylene glycol, polypropyleneglycol, glycol ether, glycerol, and polyoxyethylene alcohols.

[0062] C. Preparation of Compounds for Use in the Compositions

[0063] The preparation of the compounds used in the compositionsprovided herein is described below. Any such compound or similarcompound may be synthesized according to a method discussed in generalbelow or by only minor modification of the methods by selectingappropriate starting materials.

[0064] Formoterol may be prepared according to the method disclosed inU.S. Pat. No. 3,994,974. Briefly,4-benzyloxy-3-nitro-α-bromoacetophenone is reacted withN-benzyl-N-(1-methyl-2-p-methoxyphenylethyl)amine to form theα-aminoacetophenone. This compound was subjected to the following seriesof reactions: (i) reduction of the ketone with sodium borohydride; (ii)reduction of the nitro group with aqueous hydrochloric acid and ironpowder; (iii) amine formulation with acetic anhydride and formic acid;and (iv) catalytic reduction over 10% palladium on carbon to affordformoterol free base. Crystallization of the ½ fumarate salt fromethanol provides (formoterol).½ fumarate.

[0065] The individual enantiomers of formoterol,2-hydroxy-5-((1S)-1-hydroxy-2-(((1S)-2-(p-methoxyphenyl)-1-methylethyl)amino)ethyl)-formanilide and2-hydroxy-5-((1R)-1-hydroxy-2-(((1R)-2-(p-methoxyphenyl)-1-methylethyl)amino)ethyl)formanilide,may be prepared by the method disclosed in U.S. Pat. No. 6,040,344.Briefly, reaction of optically pure 4-benzyloxy-3-formamidostyrene oxidewith an optically pure4-methoxy-α-methyl-N-(phenylmethyl)benzeneethanamine, followed bydebenzylation, affords the desired enantiomer of formoterol.Debenzylation may be accomplished by reduction with hydrogen gas in thepresence of a noble metal catalyst, such as palladium on carbon.

[0066] The required optically pure 4-benzyloxy-3-formamidostyrene oxidemay be prepared from 4-benzyloxy-3-nitro-α-bromoacetophenone by (i)reduction with vorane in the presence of an optically pure aminoindanol,(ii) hydrogenation over platinum oxide catalyst, (iii) formylation withformic acid and acetic anhydride, and (iv) epoxide formation in thepresence of potassium carbonate.

[0067] The required optically pure4-methoxy-i-methyl-N-(phenylmethyl)-benzeneethanamine may be preparedfrom 4-methoxyphenylacetone by (i) reductive amination with benzylaminein the presence of hydrogen and a platinum catalyst, and (ii)crystallization of the desired optically pure amine from the resultingracemic mixture as its mandelic acid salt.

[0068] D. Formulation of Pharmaceutical Compositions

[0069] The compositions provided herien are prepared by procedures wellknown to those of skill in the art. For example, a formoterol fumaratesolution may be prepared by the procedure of EXAMPLE 1. Briefly, abuffer solution having a pH and ionic strength of interest herein isprepared. In one embodiment, the buffer is a mixture of citric acid andsodium citrate, with sodium chloride added to achieve the desired ionicstrength. Formoterol fumarate dihydrate is added to the buffer solutionwith agitation to produce a solution of the desired formoterolconcentration. Exemplary formoterol concentrations are 0.17 g formoterolfumarate dihydrate/2 L and 0.34 g formoterol fumarate dihydrate/2 Lbuffer.

[0070] E. Evaluation of the Activity of the Compositions

[0071] Standard physiological, pharmacological and biochemicalprocedures are available for testing the compositions provided herein toidentify those that possess bronchdilatory activity.

[0072] In vitro and in vivo assays that may be used to evaluatebronchodilatory activity are well known to those of skill in the art.See also, e.g., U.S. Pat. Nos. 3,994,974, and 6,068,833; German PatentNo. 2,305,092; Kaumann et al. (1985) Naunyn-Schmied Arch. Pharmacol.331:27-39; Lemoine et al. (1985) Naunyn-Schmied Arch. Pharmacol.331:40-51; Tomioka et al. (1981) Arch. Int. Pharmacodyn. 250:279-292;Dellamary et al. (2000) Pharm. Res. 17(2):168-174; Rico-Mendez et al.(1999) Rev. Alerg. Mex. 46(5):130-135; Seberova et al. (2000) Respir.Med. 94(6):607-611; Lotvall et al. (1999) Can. Respir. J. 6(5):412-416;Campbell et al. (1999) Respir. Med. 93(4):236-244; Nightingale et al.(1999) Am. J. Respir. Crit. Care Med. 159(6):1786-1790; Lecaillon et al(1999) Eur. J. Clin. Pharmacol. 55(2):131-138; Bartow et al. (1998)Drugs 55(2):303-322; Ekstrom et al. (1998) Respir. Med. 92(8):1040-1045;Ringdal et al. (1998) Respir. Med. 92(8):1017-1021; Totterman et al.(1998) Eur. Respir. J. 12(3):573-579; Palmqvist et al. (1997) Eur.Respir. J. 10(11):2484-2489; Nielsen et al. (1997) Eur. Respir. J.10(9):2105-2109; Ullman et al. (1996) Allergy 51(10):745-748; Selroos etal. (1996) Clin. Immunother. 6:273-299; and Schreurs et al. (1996) Eur.Respir. J. 9(8):1678-1683.

[0073] F. Methods of Treatment of Bronchoconstrictive Disorders

[0074] The compositions provided herein are used for treating,preventing, or ameliorating one or more symptoms of abronchoconstrictive disorders in a subject. In one embodiment, themethod includes administering to a subject an effective amount of acomposition containing a bronchodilating agent, including, but notlimited to, formoterol, whereby the disease or disorder is treated orprevented. The subject treated is, in certain embodiments, a mammal. Themammal treated is, in certain embodiments, a human.

[0075] In another embodiment, the method provided herein includes oraladministration of a composition provided herein. In certain embodimentsherein, the composition is directly administered to a subject in need ofsuch treatment via nebulization without dilution or other modificationof the composition prior to administration.

[0076] The methods for treatment, prevention, or amelioration of one ormore symptoms of bronchoconstrictive disorders, in another embodiment,further include administering one or more of (a), (b), (c) or (d) asfollows: (a) a β₂-adrenoreceptor agonist; (b) a dopamine (D₂) receptoragonist; (c) a prophylactic therapeutic, such as a steroid; or (d) ananticholinergic agent; simultaneously with, prior to or subsequent tothe composition provided herein.

[0077] β₂-Adrenoreceptor agonists for use in combination with thecompositions provided herein include, but are not limited to, Albuterol(α¹-(((1,1-dimethylethyl)amino)methyl)-4-hydroxy-1,3-benzenedimethanol);Bambuterol (dimethylcarbamic acid5-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,3-phenylene ester);Bitolterol (4-methylbenzoic acid4-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,2-phenylene ester);Broxaterol(3-bromo-α-(((1,1-dimethylethyl)amino)methyl)-5-isoxazolemethanol);Isoproterenol(4-(1-hydroxy-2-((1-methylethyl)amino)ethyl)-1,2-benzenediol);Trimetoquinol(1,2,3,4-tetrahydro-1-((3,4,5-trimethoxyphenyl)-methyl)-6,7-isoquinolinediol);Clenbuterol(4-amino-3,5-dichloro-α-(((1,1-diemthylethyl)amino)methyl)benzenemethanol);Fenoterol(5-(1-hydroxy-2-((2-(4-hydroxyphenyl)-1-methylethyl)amino)ethyl)-1,3-benzenediol);Formoterol(2-hydroxy-5-((1RS)-1-hydroxy-2-(((1RS)-2-(p-methoxyphenyl)-1-methylethyl)amino)ethyl)formanilide);(R,R)-Formoterol; Desformoterol ((R,R) or(S,S)-3-amino-4-hydroxy-α-(((2-(4-methoxyphenyl)-1-methylethyl)amino)methyl)benzenemethanol);Hexoprenaline(4,4′-(1,6-hexanediyl)-bis(imino(1-hydroxy-2,1-ethanediyl)))bis-1,2-benzenediol);Isoetharine(4-(1-hydroxy-2-((1-methylethyl)amino)butyl)-1,2-benzenediol);Isoprenaline(4-(1-hydroxy-2-((1-methylethyl)amino)ethyl)-1,2-benzenediol);Metaproterenol(5-(1-hydroxy-2-((1-methylethyl)amino)ethyl)-1,3-benzenediol);Picumeterol(4-amino-3,5-dichloro-α-(((6-(2-(2-pyridinyl)ethoxy)hexyl)-amino)methyl)benzenemethanol);Pirbuterol(α⁶-(((1,1-dimethylethyl)-amino)methyl)-3-hydroxy-2,6-pyridinemethanol);Procaterol(((R*,S*)-(±)-8-hydroxy-5-(1-hydroxy-2-((1-methylethyl)amino)butyl)-2(1H)-quinolinone);Reproterol((7-(3-((2-(3,5-dihydroxyphenyl)-2-hydroxyethyl)amino)-propyl)-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione);Rimiterol (4-(hydroxy-2-piperidinylmethyl)-1,2-benzenediol); Salbutamol((±)-α¹-(((1,1-dimethylethyl)amino)methyl)-4-hydroxy-1,3-benzenedimethanol);(R)-Salbutamol; Salmeterol((±)-4-hydroxy-α¹′-(((6-(4-phenylbutoxy)hexyl)-amino)methyl)-1,3-benzenedimethanol);(R)-Salmeterol; Terbutaline(5-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,3-benzenediol);Tulobuterol(2-chloro-α-(((1,1-dimethylethyl)amino)methyl)benzenemethanol); andTA-2005(8-hydroxy-5-((1R)-1-hydroxy-2-(N-((1R)-2-(4-methoxyphenyl)-1-methylethyl)amino)ethyl)carbostyrilhydrochloride).

[0078] Dopamine (D₂) receptor agonists include, but are not limited to,Apomorphine((r)-5,6,6a,7-tetrahydro-6-methyl-4H-dibenzo[de,g]quinoline-10,11-diol);Bromocriptine((5′α)-2-bromo-12′-hydroxy-2′-(1-methylethyl)-5′-(2-methylpropyl)ergotaman-3′,6′, 18-trione); Cabergoline((8,β)-N-(3-(dimethylamino)propyl)-N-((ethylamino)carbonyl)-6-(2-propenyl)ergoline-8-carboxamide);Lisuride(N′-((8α)-9,10-didehydro-6-methylergolin-8-yl)-N,N-diethylurea);Pergolide ((8β)-8-((methylthio)methyl)-6-propylergoline); Levodopa(3-hydroxy-L-tryrosine); Pramipexole((s)-4,5,6,7-tetrahydro-N⁶-propyl-2,6-benzothiazolediamine); Quinpirolehydrochirodie(trans-(−)-4aR-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo[3,4-g]quinolinehydrochloride); Ropinirole(4-(2-(dipropylamino)ethyl)-1,3-dihydro-2H-indol-2-one); and Talipexole(5,6,7,8-tetrahydro-6-(2-propenyl)-4H-thiazolo[4,5-d]azepin-2-amine).Other dopamine D₂ receptor agonists for use herein are disclosed inInternational Patent Application Publication No. WO 99/36095.

[0079] Prophylactic therapeutics for use in combination therapy hereininclude steroidal anti-inflammatory agents, including, but not limitedto, beclomethasone dipropionate (BDP), beclomethasone monopropionate(BMP), flunisolide, triamcinolone acetonide, dexamethasone, tipredane,ciclesonid, rofleponide, mometasone, mometasone furoate (Asmanex®Twisthaler®, Shering-Plough Corporation, Kenilworth, N.J.), RPR 106541,fluticasone or fluticasone propionate and budesonide or by way of sodiumcromoglycate or nedocromil sodium.

[0080] Anticholinergic agents for use herein include, but are notlimited to, ipratropium bromide, oxitropium bromide, atropine methylnitrate, atropine sulfate, ipratropium, belladonna extract, scopolamine,scopolamine methobromide, homatropine methobromide, hyoscyamine,isopriopramide, orphenadrine, benzalkonium chloride, tiotropium bromideand glycopyrronium bromide. In certain embodiments, the compositionscontain an anticholinergic agent, such as ipratropium bromide ortiotropium bromide, at a concentration of about 5 μg/mL to about 5mg/mL, or about 50 μg/mL to about 200 μg/mL. In other embodiments, thecompositions for use in the methods herein contain an anticholinergicagent, including ipratropium bromide and tiotropium bromide, at aconcentration of about 83 μg/mL or about 167 μg/mL.

[0081] Other active ingredients for use herein in combination therapy,include, but are not limited to, IL-5 inhibitors such as those disclosedin U.S. Pat. Nos. 5,668,110, 5,683,983, 5,677,280 and 5,654,276;antisense modulators of IL-5 such as those disclosed in U.S. Pat. No.6,136,603; milrinone(1,6-dihydro-2-methyl-6-oxo-[3,4′-bipyridine]-5-carbonitrile); milrinonelactate; tryptase inhibitors such as those disclosed in U.S. Pat. No.5,525,623; tachykinin receptor antagonists such as those disclosed inU.S. Pat. Nos. 5,691,336, 5,877,191, 5,929,094, 5,750,549 and 5,780,467;leukotriene receptor antagonists such as montelukast sodium (Singular®,R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl)phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]-propyl]thio]methyl]cyclopropaneaceticacid, monosodium salt), 5-lypoxygenase inhibitors such as zileuton(Zyflo®, Abbott Laboratories, Abbott Park, Ill.), and anti-IgEantibodies such as Xolair® (recombinant humanized anti-IgE monoclonalantibody (CGP 51901; IGE 025A; rhuMAb-E25), Genentech, Inc., South SanFrancisco, Calif.).

[0082] The bronchoconstrictive disorder to be treated, prevented, orwhose one or more symptoms are to be ameliorated is associated withasthma, including, but not limited to, bronchial asthma, allergic asthmaand intrinsic asthma, e.g., late asthma and airway hyper-responsiveness;and, particularly in embodiments where an anticholinergic agent is used,other chronic obstructive pulmonary diseases (COPDs), including, but notlimited to, chronic bronchitis, emphysema, and associated cor pulmonale(heart disease secondary to disease of the lungs and respiratory system)with pulmonary hypertension, right ventricular hypertrophy and rightheart failure. COPD is frequently associated with cigarette smoking,infections, environmental pollution and occupational dust exposure.

[0083] G. Nebulizers

[0084] The compositions provided herein are intended for administrationto a subject in need of such treatment via nebulization. Nebulizers thatnebulize liquid formulations containing no propellant are suitable foruse with the compositions provided herein. Nebulizers are availablefrom, e.g., Pari GmbH (Starnberg, Germany), DeVilbiss Healthcare(Heston, Middlesex, UK), Healthdyne, Vital Signs, Baxter, Allied HealthCare, Invacare, Hudson, Omron, Bremed, AirSep, Luminscope, Medisana,Siemens, Aerogen, Mountain Medical, Aerosol Medical Ltd. (Colchester,Essex, UK), AFP Medical (Rugby, Warwickshire, UK), Bard Ltd.(Sunderland, UK), Carri-Med Ltd. (Dorking, UK), Plaem Nuiva (Brescia,Italy), Henleys Medical Supplies (London, UK), Intersurgical (Berkshire,UK), Lifecare Hospital Supplies (Leies, UK), Medic-Aid Ltd. (WestSussex, UK), Medix Ltd. (Essex, UK), Sinclair Medical Ltd. (Surrey, UK),and many others.

[0085] Nebulizers for use herein include, but are not limited to, jetnebulizers (optionally sold with compressors), ultrosonic nebulizers,and others. Exemplary jet nebulizers for use herein include Pari LCplus/ProNeb, Pari LC plus/ProNeb Turbo, Pari LC plus/Dura Neb 1000 &2000, Pari LC plus/Walkhaler, Pari LC plus/Pari Master, Pari LC star,Omron CompAir XL Portable Nebulizer System (NE-C18 and JetAir Disposablenebulizer), Omron CompAir Elite Compressor Nebulizer System (NE-C21 andElite Air Reusable Nebilizer), Pari LC Plus or Pari LC Star nebulizerwith Proneb Ultra compressor, Pulmo-aide, Pulmo-aide LT, Pulmo-aidetraveler, Invacare Passport, Inspiration Healthdyne 626, Pulmo-NebTraverler, DeVilbiss 646, Whisper Jet, Acorn II, Misty-Neb, Alliedaerosol, Schuco Home Care, Lexan Plasic Pocet Neb, SideStream Hand HeldNeb, Mobil Mist, Up-Draft, Up-Draft II, T Up-Draft, ISO-NEB, AVA-NEB,Micro Mist, and PulmoMate. Exemplary ultrasonic nebulizers for useherein include MicroAir, UltraAir, Siemens Ultra Nebulizer 145, CompAir,Pulmosonic, Scout, 5003 Ultrasonic Neb, 5110 Ultrasonic Neb, 5004 DeskUltrasonic Nebulizer, Mystique Ultrasonic, Luminscope's UltrasonicNebulizer, Medisana Ultrasonic Nebulizer, Microstat UltrasonicNebulizer, and MABISMist Hand Held Ultrasonic Nebulizer. Othernebulizers for use herein include 5000 Electromagnetic Neb, 5001Electromagnetic Neb 5002 Rotary Piston Neb, Lumineb I Piston Nebulizer5500, Aeroneb™ Portable Nebulizer System, Aerodose™ Inhaler, andAeroEclipse Breath Actuated Nebulizer.

[0086] H. Articles of Manufacture

[0087] The compositions provided herein may be packaged as articles ofmanufacture containing packaging material, a composition providedherein, which is useful for treatment, prevention or amelioration of oneor more symptoms of diseases or disorders associated with undesiredand/or uncontrolled bronchoconstriction, and a label that indicates thatthe composition is used for treatment, prevention or amelioration of oneor more symptoms of diseases or disorders associated with undesiredand/or uncontrolled bronchoconstriction.

[0088] The articles of manufacture provided herein contain packagingmaterials. Packaging materials for use in packaging pharmaceuticalproducts are well known to those of skill in the art. See, e.g., U.S.Pat. Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceuticalpackaging materials include, but are not limited to, blister packs,bottles, tubes, inhalers, pumps, bags, vials, containers, syringes,bottles, and any packaging material suitable for a selected formulationand intended mode of administration and treatment.

[0089] In one embodiment herein, the compositions are packaged with anebulizer for direct administration of the composition to a subject inneed thereof.

[0090] The following examples are included for illustrative purposesonly and are not intended to limit the scope of the invention.

EXAMPLE 1

[0091] Preparation of Formoterol Inhalation Solution Formulation

[0092] To a 5 L stainless steel vessel were added 0.68 g citric acidUSP, 1.99 g sodium citrate USP, and 17.5 g sodium chloride USP. Purifiedwater USP (2 L) was added to the stainless steel vessel and the contentswere mixed with an overhead stirrer at a speed of 240 rpm for 10minutes. Formoterol fumarate dihydrate (0.17 g for low dosage strengthformulation, 0.34 g for high dosage strength formulation) was added andthe solution was stirred at 240 rpm for 90 minutes.

EXAMPLE 2

[0093] Preparation of Formoterol Unit Dose Formulations

[0094] Following the procedure of EXAMPLE 1, the following formoterolunit dose formulations were prepared.

[0095] Low Strength (0.0085%)

[0096] A low strength formoterol unit dose formulation was preparedusing the following reagents in the amounts indicated: formoterolfumarate dihydrate (0.170 mg), citric acid monohydrate, USP (0.68 mg),sodium citrate dihydrate, USP (1.99 mg), sodium chloride, USP (17.5 mg),and purified water, USP (qs to 2 mL).

[0097] High Strength (0.0170%)

[0098] A high strength formoterol unit dose formulation was preparedusing the following reagents in the amounts indicated: formoterolfumarate dihydrate (0.340 mg), citric acid monohydrate, USP (0.68 mg),sodium citrate dihydrate, USP (1.99 mg), sodium chloride, USP (17.5 mg),and purified water, USP (qs to 2 mL).

EXAMPLE 3

[0099] Procedure for Stability Testing of Formoterol Solutions

[0100] Stability samples of the solutions prepared in EXAMPLES 1 and 2were placed in scintillation vials with teflon-lined caps and stored instability ovens at accelerated temperatures. At selected time points,aliquots of the samples were removed from the scintillation vials. Theformoterol concentrations of the samples were analyzed by highperformance liquid chromatography.

[0101] Since modifications will be apparent to those of skill in thisart, it is intended that this invention be limited only by the scope ofthe appended claims.

What is claimed is:
 1. A kit, comprising: (a) an aqueous compositioncomprising formoterol or a derivative thereof formulated for singledosage administration; and (b) a nebulizer.
 2. The kit of claim 1,wherein the composition has an estimated shelf-life of greater than 1month usage time at 25° C. and greater than or equal to 1 year storagetime at 5° C.
 3. The kit of claim 2, wherein greater than about 80% ofthe initial formoterol is present after 1 month usage time at 25° C. and1 year storage time at 5° C.
 4. The kit of claim 1, wherein thecomposition further comprises a polar solvent.
 5. The kit of claim 4,wherein the polar solvent is a protic solvent.
 6. The kit of claim 5,wherein the composition further comprises a tonicity adjusting agent. 7.The kit of claim 6, wherein the tonicity adjusting agent is ammoniumcarbonate, ammonium chloride, ammonium lactate, ammonium nitrate,ammonium phosphate, ammonium sulfate, ascorbic acid, bismuth sodiumtartrate, boric acid, calcium chloride, calcium disodium edetate,calcium gluconate, calcium lactate, citric acid, dextrose,diethanolamine, dimethylsulfoxide, edetate disodium, edetate trisodiummonohydrate, fluorescein sodium, fructose, galactose, glycerin, lacticacid, lactose, magnesium chloride, magnesium sulfate, mannitol,polyethylene glycol, potassium acetate, potassium chlorate, potassiumchloride, potassium iodide, potassium nitrate, potassium phosphate,potassium sulfate, proplyene glycol, silver nitrate, sodium acetate,sodium bicarbonate, sodium biphosphate, sodium bisulfite, sodium borate,sodium bromide, sodium cacodylate, sodium carbonate, sodium chloride,sodium citrate, sodium iodide, sodium lactate, sodium metabisulfite,sodium nitrate, sodium nitrite, sodium phosphate, sodium propionate,sodium succinate, sodium sulfate, sodium sulfite, sodium tartrate,sodium thiosulfate, sorbitol, sucrose, tartaric acid, triethanolamine,urea, urethan, uridine or zinc sulfate.
 8. The kit of claim 7, whereinthe tonicity adjusting agent is sodium chloride.
 9. The kit of claim 1,wherein the composition further comprises a buffer.
 10. The kit of claim9, wherein the buffer is citric acid/phosphate, acetate, barbital,borate, Britton-Robinson, cacodylate, citrate, collidine, formate,maleate, Mcllvaine, phosphate, Prideaux-Ward, succinate,citrate-phosphate-borate (Teorell-Stanhagen), veronal acetate, MES(2-(N-morpholino)ethanesulfonic acid), BIS-TRIS(bis(2-hydroxyethyl)iminotris(hydroxymethyl)methane), ADA(N-(2-acetamido)-2-iminodiacetic acid), ACES(N-(carbamoylmethyl)-2-aminoethanesulfonaic acid), PIPES(piperazine-N,N′-bis(2-ethanesulfonic acid)), MOPSO(3-(N-morpholino)-2-hydroxypropanesulfonic acid), BIS-TRIS PROPANE(1,3-bis(tris(hydroxymethyl)methylamino)propane), BES(N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonaic acid), MOPS(3-(N-morpholino)propanesulfonic acid), TES(N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid), HEPES(N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid), DIPSO(3-(N,N-bis(2-hydroxyethyl)amino)-2-hydroxypropanesulfonic acid), MOBS(4-(N-morpholino)butanesulfonic acid), TAPSO(3-(N-tris(hydroxymethyl)methylamino)-2-hydroxypropanesulfonic acid),tris(hydroxymethylaminomethane, HEPPSO(N-(2-hydroxyethyl)piperazine-N′-(2-hydroxypropanesulfonicacid), POPSO(piperazine-N,N′-bis(2-hydroxypropanesulfonic acid)), TEA(triethanolamine), EPPS(N-(2-hydroxyethyl)piperazine-N′-(3-propanesulfonic acid), TRICINE(N-tris(hydroxymethyl)methylglycine), GLY-GLY (glycylglycine), BICINE(N,N-bis(2-hydroxyethyl)glycine), HEPBS(N-(2-hydroxyethyl)piperazine-N′-(4-butanesulfonic acid)), TAPS(N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid), or AMPD(2-amino-2-methyl-1,3-propanediol) buffer.
 11. The kit of claim 10,wherein the buffer is citrate buffer.
 12. The kit of claim 11, whereinthe buffer concentration is from about 0.01 mM to about 150 mM.
 13. Thekit of claim 12, wherein the buffer concentration is from about 1 mM toabout 20 mM.
 14. The kit of claim 13, wherein the buffer concentrationis about 5 mM.
 15. The kit of claim 7, wherein the ionic strength of thecomposition is about 0 to about 0.4.
 16. The kit of claim 15, whereinthe ionic strength of the composition is about 0.05 to about 0.16. 17.The kit of claim 1, wherein the pH of the composition is about 2.0 toabout 8.0.
 18. The kit of claim 17, wherein the pH of the composition isabout 4.0 to about 6.0.
 19. The kit of claim 18, wherein the pH of thecomposition is about 4.5 to about 5.5.
 20. The kit of claim 19, whereinthe pH of the composition is about 5.0.
 21. The kit of claim 1, whereinthe formoterol free base concentration in the composition is about 5μg/mL to about 2 mg/mL.
 22. The kit of claim 21, wherein the formoterolfree base concentration in the composition is about 10 μg/mL to about 1mg/mL.
 23. The kit of claim 22, wherein the formoterol free baseconcentration in the composition is about 50 μg/mL to about 200 μg/mL.24. The kit of claim 23, wherein the formoterol free base concentrationin the composition is about 59 μg/mL.
 25. The kit of claim 23, whereinthe formoterol free base concentration in the composition is about 118μg/mL.
 26. The kit of claim 7, wherein the composition further comprisesa buffer.
 27. The kit of claim 26, wherein the buffer is citricacid/phosphate, acetate, barbital, borate, Britton-Robinson, cacodylate,citrate, collidine, formate, maleate, Mcllvaine, phosphate,Prideaux-Ward, succinate, citrate-phosphate-borate (Teorell-Stanhagen),veronal acetate, MES (2-(N-morpholino)ethanesulfonic acid), BIS-TRIS(bis(2-hydroxyethyl)iminotris(hydroxymethyl)methane), ADA(N-(2-acetamido)-2-iminodiacetic acid), ACES(N-(carbamoylmethyl)-2-aminoethanesulfonaic acid), PIPES(piperazine-N,N′-bis(2-ethanesulfonic acid)), MOPSO(3-(N-morpholino)-2-hydroxypropanesulfonic acid), BIS-TRIS PROPANE(1,3-bis(tris(hydroxymethyl)methylamino)propane), BES(N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonaic acid), MOPS(3-(N-morpholino)propanesulfonic acid), TES(N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid), HEPES(N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid), DIPSO(3-(N,N-bis(2-hydroxyethyl)amino)-2-hydroxypropanesulfonic acid), MOBS(4-(N-morpholino)butanesulfonic acid), TAPSO(3-(N-tris(hydroxymethyl)methylamino)-2-hydroxypropanesulfonic acid),tris(hydroxymethylaminomethane, HEPPSO(N-(2-hydroxyethyl)piperazine-N′-(2-hydroxypropanesulfonicacid), POPSO(piperazine-N,N′-bis(2-hydroxypropanesulfonic acid)), TEA(triethanolamine), EPPS(N-(2-hydroxyethyl)piperazine-N′-(3-propanesulfonic acid), TRICINE(N-tris(hydroxymethyl)methylglycine), GLY-GLY (glycylglycine), BICINE(N,N-bis(2-hydroxyethyl)glycine), HEPBS(N-(2-hydroxyethyl)piperazine-N′-(4-butanesulfonic acid)), TAPS(N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid), or AMPD(2-amino-2-methyl-1,3-propanediol) buffer.
 28. The kit of claim 27,wherein the buffer is citrate buffer.
 29. The kit of claim 28, whereinthe buffer concentration is from about 0.01 mM to about 150 mM.
 30. Thekit of claim 29, wherein the buffer concentration is from about 1 mM toabout 20 mM.
 31. The kit of claim 30, wherein the buffer concentrationis about 5 mM.
 32. The kit of claim 26, wherein the ionic strength ofthe composition is about 0 to about 0.4.
 33. The kit of claim 32,wherein the ionic strength of the composition is about 0.05 to about0.16.
 34. The kit of claim 26, wherein the pH of the composition isabout 2.0 to about 8.0.
 35. The kit of claim 34, wherein the pH of thecomposition is about 4.0 to about 6.0.
 36. The kit of claim 35, whereinthe pH of the composition is about 4.5 to about 5.5.
 37. The kit ofclaim 36, wherein the pH of the composition is about 5.0.
 38. The kit ofclaim 26, wherein the formoterol free base concentration in thecomposition is about 5 μg/mL to about 2 mg/mL.
 39. The kit of claim 38,wherein the formoterol free base concentration in the composition isabout 10 μg/mL to about 1 mg/mL.
 40. The kit of claim 39, wherein theformoterol free base concentration in the composition is about 50 μg/mLto about 200 μg/mL.
 41. The kit of claim 40, wherein the formoterol freebase concentration in the composition is about 59 μg/mL.
 42. The kit ofclaim 40, wherein the formoterol free base concentration in thecomposition is about 118 μg/mL.
 43. The kit of claim 1, wherein theaqueous composition comprises (a) formoterol free base at aconcentration of about 59 μg/mL; (b) aqueous saline comprising sodiumchloride; and (c) citrate buffer at a concentration of about 5 mM;wherein the ionic strength of the composition is about 0.05 to about0.16; and the pH of the composition is about 5.0.
 44. The kit of claim1, wherein the aqueous composition comprises (a) formoterol free base ata concentration of about 118 μg/mL; (b) aqueous saline comprising sodiumchloride; and (c) citrate buffer at a concentration of about 5 mM;wherein the ionic strength of the composition is about 0.05 to about0.16; and the pH of the composition is about 5.0.
 45. The kit of claim1, wherein the aqueous composition comprises (a) formoterol free base ata concentration of about 59 μg/mL; (b) aqueous saline comprising sodiumchloride; and (c) citrate buffer at a concentration of about 20 mM;wherein the ionic strength of the composition is about 0.05 to about0.16; and the pH of the composition is about 5.0.
 46. The kit of claim1, wherein the aqueous composition comprises (a) formoterol free base ata concentration of about 118 μg/mL; (b) aqueous saline comprising sodiumchloride; and (c) citrate buffer at a concentration of about 20 mM;wherein the ionic strength of the composition is about 0.05 to about0.16; and the pH of the composition is about 5.0.
 47. The kit of claim41, wherein the buffer is citrate buffer.
 48. The kit of claim 41,wherein the buffer concentration is about 5 mM.
 49. The kit of claim 41,wherein the ionic strength of the composition is about 0.05 to about0.16.
 50. The kit of claim 41, wherein the pH of the composition isabout 5.0.
 51. The kit of claim 41, wherein the buffer is citratebuffer; the buffer concentration is about 5 mM; the ionic strength ofthe composition is about 0.05 to about 0.16; and the pH of thecomposition is about 5.0.
 52. The kit of claim 42, wherein the buffer iscitrate buffer.
 53. The kit of claim 42, wherein the bufferconcentration is about 5 mM.
 54. The kit of claim 42, wherein the ionicstrength of the composition is about 0.05 to about 0.16.
 55. The kit ofclaim 42, wherein the pH of the composition is about 5.0.
 56. The kit ofclaim 42, wherein the buffer is citrate buffer; the buffer concentrationis about 5 mM; the ionic strength of the composition is about 0.05 toabout 0.16; and the pH of the composition is about 5.0.
 57. The kit ofclaim 1, further comprising one or more of (a) to (j) as follows: (a) aβ₂-adrenoreceptor agonist; (b) a dopamine (D₂) receptor agonist; (c) anIL-5 inhibitor; (d) an antisense modulator of IL-5; (e) a tryptaseinhibitor; (f) a tachykinin receptor antagonist; (g) milrinone ormilrinone lactate; (h) a leukotriene receptor antagonist; (i) a5-lypoxygenase inhibitor; or (j) an anti-IgE antibody.
 58. The kit ofclaim 10, wherein the buffer comprises citric acid/phosphate buffer,acetate buffer, citrate buffer or phosphate buffer.
 59. The kit of claim26, wherein the buffer comprises citric acid/phosphate buffer, acetatebuffer, citrate buffer or phosphate buffer.
 60. The kit of claim 12,wherein the buffer concentration is from about 1 mM to about 50 mM. 61.The kit of claim 60, wherein the buffer concentration is about 20 mM.62. The kit of claim 29, wherein the buffer concentration is from about1 mM to about 50 mM.
 63. The kit of claim 62, wherein the bufferconcentration is about 20 mM.
 64. The kit of claim 41, wherein thebuffer concentration is about 20 mM.
 65. The kit of claim 41, whereinthe buffer is citrate buffer; the buffer concentration is about 20 mM;the ionic strength of the composition is about 0.05 to about 0.16; andthe pH of the composition is about 5.0.
 66. The kit of claim 42, whereinthe buffer concentration is about 20 mM.
 67. The kit of claim 42,wherein the buffer is citrate buffer; the buffer concentration is about20 mM; the ionic strength of the composition is about 0.05 to about0.16; and the pH of the composition is about 5.0.
 68. The kit of claim1, further comprising an anticholinergic agent.
 69. The kit of claim 68,wherein the anticholinergic agent is ipratropium bromide, oxitropiumbromide, atropine methyl nitrate, tiotropium bromide or glycopyrroniumbromide.
 70. The kit of claim 69, wherein the anticholinergic agent isipratropium bromide.
 71. The kit of claim 70, wherein the ipratropiumbromide is present at a concentration of about 5 μg/mL to about 5 mg/mL.72. The kit of claim 69, wherein the anticholinergic agent is tiotropiumbromide.
 73. The kit of claim 72, wherein the tiotropium bromide ispresent at a concentration of about 5 μg/mL to about 5 mg/mL.
 74. Amethod for the treatment, prevention, or amelioration of one or moresymptoms of bronchoconstrictive disorders, comprising administering aneffective amount of a pharmaceutical composition to a subject in need ofsuch treatment, wherein the pharmaceutical composition comprisesformoterol, or a derivative thereof, in a pharmacologically suitablefluid, wherein the composition is stable during long term storage andthe fluid comprises water.
 75. The method of claim 74, wherein thecomposition has an estimated shelf-life of greater than 1 month usagetime at 25° C. and greater than or equal to 1 year storage time at 5° C.76. The method of claim 75, wherein greater than about 80% of theinitial formoterol is present after 1 month usage time at 25° C. and 1year storage time at 5° C.
 77. The method of claim 74, wherein thecomposition further comprises a polar solvent.
 78. The method of claim77, wherein the polar solvent is a protic solvent.
 79. The method ofclaim 78, wherein the composition further comprises a tonicity adjustingagent.
 80. The method of claim 79, wherein the tonicity adjusting agentis ammonium carbonate, ammonium chloride, ammonium lactate, ammoniumnitrate, ammonium phosphate, ammonium sulfate, ascorbic acid, bismuthsodium tartrate, boric acid, calcium chloride, calcium disodium edetate,calcium gluconate, calcium lactate, citric acid, dextrose,diethanolamine, dimethylsulfoxide, edetate disodium, edetate trisodiummonohydrate, fluorescein sodium, fructose, galactose, glycerin, lacticacid, lactose, magnesium chloride, magnesium sulfate, mannitol,polyethylene glycol, potassium acetate, potassium chlorate, potassiumchloride, potassium iodide, potassium nitrate, potassium phosphate,potassium sulfate, proplyene glycol, silver nitrate, sodium acetate,sodium bicarbonate, sodium biphosphate, sodium bisulfite, sodium borate,sodium bromide, sodium cacodylate, sodium carbonate, sodium chloride,sodium citrate, sodium iodide, sodium lactate, sodium metabisulfite,sodium nitrate, sodium nitrite, sodium phosphate, sodium propionate,sodium succinate, sodium sulfate, sodium sulfite, sodium tartrate,sodium thiosulfate, sorbitol, sucrose, tartaric acid, triethanolamine,urea, urethan, uridine or zinc sulfate.
 81. The method of claim 80,wherein the tonicity adjusting agent is sodium chloride.
 82. The methodof claim 74, wherein the composition further comprises a buffer.
 83. Themethod of claim 82, wherein the buffer is citric acid/phosphate,acetate, barbital, borate, Britton-Robinson, cacodylate, citrate,collidine, formate, maleate, Mcllvaine, phosphate, Prideaux-Ward,succinate, citrate-phosphate-borate (Teorell-Stanhagen), veronalacetate, MES (2-(N-morpholino)ethanesulfonic acid), BIS-TRIS(bis(2-hydroxyethyl)iminotris(hydroxymethyl)methane), ADA(N-(2-acetamido)-2-iminodiacetic acid), ACES(N-(carbamoylmethyl)-2-aminoethanesulfonaic acid), PIPES(piperazine-N,N′-bis(2-ethanesulfonic acid)), MOPSO(3-(N-morpholino)-2-hydroxypropanesulfonic acid), BIS-TRIS PROPANE(1,3-bis(tris(hydroxymethyl)methylamino)propane), BES(N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonaic acid), MOPS(3-(N-morpholino)propanesulfonic acid), TES(N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid), HEPES(N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid), DIPSO(3-(N,N-bis(2-hydroxyethyl)amino)-2-hydroxypropanesulfonic acid), MOBS(4-(N-morpholino)butanesulfonic acid), TAPSO(3-(N-tris(hydroxymethyl)methylamino)-2-hydroxypropanesulfonic acid),tris(hydroxymethylaminomethane, HEPPSO(N-(2-hydroxyethyl)piperazine-N′-(2-hydroxypropanesulfonicacid), POPSO(piperazine-N,N′-bis(2-hydroxypropanesulfonic acid)), TEA(triethanolamine), EPPS(N-(2-hydroxyethyl)piperazine-N′-(3-propanesulfonic acid), TRICINE(N-tris(hydroxymethyl)methylglycine), GLY-GLY (glycylglycine), BICINE(N,N-bis(2-hydroxyethyl)glycine), HEPBS(N-(2-hydroxyethyl)piperazine-N′-(4-butanesulfonic acid)), TAPS(N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid), or AMPD(2-amino-2-methyl-1,3-propanediol) buffer.
 84. The method of claim 83,wherein the buffer is citrate buffer.
 85. The method of claim 84,wherein the buffer concentration is from about 0.01 mM to about 150 mM.86. The method of claim 85, wherein the buffer concentration is fromabout 1 mM to about 20 mM.
 87. The method of claim 86, wherein thebuffer concentration is about 5 mM.
 88. The method of claim 87, whereinthe ionic strength of the composition is about 0 to about 0.4.
 89. Themethod of claim 88, wherein the ionic strength of the composition isabout 0.05 to about 0.16.
 90. The method of claim 74, wherein the pH ofthe composition is about 2.0 to about 8.0.
 91. The method of claim 90,wherein the pH of the composition is about 4.0 to about 6.0.
 92. Themethod of claim 91, wherein the pH of the composition is about 4.5 toabout 5.5.
 93. The method of claim 92, wherein the pH of the compositionis about 5.0.
 94. The method of claim 74, wherein the formoterol freebase concentration in the composition is about 5 μg/mL to about 2 mg/mL.95. The method of claim 94, wherein the formoterol free baseconcentration in the composition is about 10 μg/mL to about 1 mg/mL. 96.The method of claim 95, wherein the formoterol free base concentrationin the composition is about 50 μg/mL to about 200 μg/mL.
 97. The methodof claim 96, wherein the formoterol free base concentration in thecomposition is about 59 μg/mL.
 98. The method of claim 96, wherein theformoterol free base concentration in the composition is about 118μg/mL.
 99. The method of claim 80, wherein the composition furthercomprises a buffer.
 100. The method of claim 99, wherein the buffer iscitric acid/phosphate, acetate, barbital, borate, Britton-Robinson,cacodylate, citrate, collidine, formate, maleate, Mcllvaine, phosphate,Prideaux-Ward, succinate, citrate-phosphate-borate (Teorell-Stanhagen),veronal acetate, MES (2-(N-morpholino)ethanesulfonic acid), BIS-TRIS(bis(2-hydroxyethyl)iminotris(hydroxymethyl)methane), ADA(N-(2-acetamido)-2-iminodiacetic acid), ACES(N-(carbamoylmethyl)-2-aminoethanesulfonaic acid), PIPES(piperazine-N,N′-bis(2-ethanesulfonic acid)), MOPSO(3-(N-morpholino)-2-hydroxypropanesulfonic acid), BIS-TRIS PROPANE(1,3-bis(tris(hydroxymethyl)methylamino)propane), BES(N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonaic acid), MOPS(3-(N-morpholino)propanesulfonic acid), TES(N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid), HEPES(N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid), DIPSO(3-(N,N-bis(2-hydroxyethyl)amino)-2-hydroxypropanesulfonic acid), MOBS(4-(N-morpholino)butanesulfonic acid), TAPSO(3-(N-tris(hydroxymethyl)methylamino)-2-hydroxypropanesulfonic acid),tris(hydroxymethylaminomethane, HEPPSO(N-(2-hydroxyethyl)piperazine-N′-(2-hydroxypropanesulfonicacid), POPSO(piperazine-N,N′-bis(2-hydroxypropanesulfonicacid)), TEA(triethanolamine), EPPS(N-(2-hydroxyethyl)piperazine-N′-(3-propanesulfonic acid), TRICINE(N-tris(hydroxymethyl)methylglycine), GLY-GLY (glycylglycine), BICINE(N,N-bis(2-hydroxyethyl)glycine), HEPBS(N-(2-hydroxyethyl)piperazine-N′-(4-butanesulfonic acid)), TAPS(N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid), or AMPD(2-amino-2-methyl-1,3-propanediol) buffer.
 101. The method of claim 100,wherein the buffer is citrate buffer.
 102. The method of claim 101,wherein the buffer concentration is from about 0.01 mM to about 150 mM.103. The method of claim 102, wherein the buffer concentration is fromabout 1 mM to about 20 mM.
 104. The method of claim 103, wherein thebuffer concentration is about 5 mM.
 105. The method of claim 99, whereinthe ionic strength of the composition is about 0 to about 0.4.
 106. Themethod of claim 105, wherein the ionic strength of the composition isabout 0.05 to about 0.16.
 107. The method of claim 99, wherein the pH ofthe composition is about 2.0 to about 8.0.
 108. The method of claim 107,wherein the pH of the composition is about 4.0 to about 6.0.
 109. Themethod of claim 108, wherein the pH of the composition is about 4.5 toabout 5.5.
 110. The method of claim 109, wherein the pH of thecomposition is about 5.0.
 111. The method of claim 99, wherein theformoterol free base concentration in the composition is about 5 μg/mLto about 2 mg/mL.
 112. The method of claim 111, wherein the formoterolfree base concentration in the composition is about 10 μg/mL to about 1mg/mL.
 113. The method of claim 112, wherein the formoterol free baseconcentration in the composition is about 50 μg/mL to about 200 μg/mL.114. The method of claim 113, wherein the formoterol free baseconcentration in the composition is about 59 μg/mL.
 115. The method ofclaim 113, wherein the formoterol free base concentration in thecomposition is about 118 μg/mL.
 116. The method of claim 74, wherein thecomposition comprises (a) formoterol free base at a concentration ofabout 59 μg/mL; (b) aqueous saline comprising sodium chloride; and (c)citrate buffer at a concentration of about 5 mM; wherein the ionicstrength of the composition is about 0.05 to about 0.16; and the pH ofthe composition is about 5.0.
 117. The method of claim 74, wherein thecomposition comprises (a) formoterol free base at a concentration ofabout 118 μg/mL; (b) aqueous saline comprising sodium chloride; and (c)citrate buffer at a concentration of about 5 mM; wherein the ionicstrength of the composition is about 0.05 to about 0.16; and the pH ofthe composition is about 5.0.
 118. The method of claim 74, wherein thecomposition comprises (a) formoterol free base at a concentration ofabout 59 μg/mL; (b) aqueous saline comprising sodium chloride; and (c)citrate buffer at a concentration of about 20 mM; wherein the ionicstrength of the composition is about 0.05 to about 0.16; and the pH ofthe composition is about 5.0.
 119. The method of claim 74, wherein thecomposition comprises (a) formoterol free base at a concentration ofabout 118 μg/mL; (b) aqueous saline comprising sodium chloride; and (c)citrate buffer at a concentration of about 20 mM; wherein the ionicstrength of the composition is about 0.05 to about 0.16; and the pH ofthe composition is about 5.0.
 120. The method of claim 113, wherein thebuffer is citrate buffer.
 121. The method of claim 113, wherein thebuffer concentration is about 5 mM.
 122. The method of claim 113,wherein the ionic strength of the composition is about 0.05 to about0.16.
 123. The method of claim 113, wherein the pH of the composition isabout 5.0.
 124. The method of claim 113, wherein the buffer is citratebuffer; the buffer concentration is about 5 mM; the ionic strength ofthe composition is about 0.05 to about 0.16; and the pH of thecomposition is about 5.0.
 125. The method of claim 114, wherein thebuffer is citrate buffer.
 126. The method of claim 114, wherein thebuffer concentration is about 5 mM.
 127. The method of claim 114,wherein the ionic strength of the composition is about 0.05 to about0.16.
 128. The method of claim 114, wherein the pH of the composition isabout 5.0.
 129. The method of claim 114, wherein the buffer is citratebuffer; the buffer concentration is about 5 mM; the ionic strength ofthe composition is about 0.05 to about 0.16; and the pH of thecomposition is about 5.0.
 130. The method of claim 74, furthercomprising administration of one or more of (a) to (j) as follows: (a) aβ₂-adrenoreceptor agonist; (b) a dopamine (D₂) receptor agonist; (c) anIL-5 inhibitor; (d) an antisense modulator of IL-5; (e) a tryptaseinhibitor; (f) a tachykinin receptor antagonist; (g) milrinone ormilrinone lactate; (h) a leukotriene receptor antagonist; (i) a5-lypoxygenase inhibitor; or (j) an anti-IgE antibody.
 131. The methodof claim 83, wherein the buffer comprises citric acid/phosphate buffer,acetate buffer, citrate buffer or phosphate buffer.
 132. The method ofclaim 99, wherein the buffer comprises citric acid/phosphate buffer,acetate buffer, citrate buffer or phosphate buffer.
 133. The method ofclaim 85, wherein the buffer concentration is from about 1 mM to about50 mM.
 134. The method of claim 133, wherein the buffer concentration isabout 20 mM.
 135. The method of claim 102, wherein the bufferconcentration is from about 1 mM to about 50 mM.
 136. The method ofclaim 135, wherein the buffer concentration is about 20 mM.
 137. Themethod of claim 114, wherein the buffer concentration is about 20 mM.138. The method of claim 114, wherein the buffer is citrate buffer; thebuffer concentration is about 20 mM; the ionic strength of thecomposition is about 0.05 to about 0.16; and the pH of the compositionis about 5.0.
 139. The method of claim 115, wherein the bufferconcentration is about 20 mM.
 140. The method of claim 115, wherein thebuffer is citrate buffer; the buffer concentration is about 20 mM; theionic strength of the composition is about 0.05 to about 0.16; and thepH of the composition is about 5.0.
 141. The method of claim 74, furthercomprising an anticholinergic agent.
 142. The method of claim 141,wherein the anticholinergic agent is ipratropium bromide, oxitropiumbromide, atropine methyl nitrate, tiotropium bromide or glycopyrroniumbromide.
 143. The method of claim 142, wherein the anticholinergic agentis ipratropium bromide.
 144. The method of claim 143, wherein theipratropium bromide is present at a concentration of about 5 μg/mL toabout 5 mg/mL.
 145. The method of claim 142, wherein the anticholinergicagent is tiotropium bromide.
 146. The method of claim 145, wherein thetiotropium bromide is present at a concentration of about 5 μg/mL toabout 5 mg/mL.